HPE Drug stability: What do we need to know? | Page 6
which is the reason why reaction rates increase and
shelf-life decreases with increasing temperature.
Hydrolysis
Hydrolysis is cleavage of chemical bonds, such as
ester and lactone bonds, by the addition of water.
It is the most common drug degradation pathway
in aqueous solutions but hydrolysis also occurs in
solid dosage forms in the presence of moisture. Acyl
groups (for example, esters, lactones, amides and
lactams) are the most common substrates that are
prone to hydrolysis, followed by imines and alkyl
halides. Hydrolysis is frequently catalysed by buffer
salts and other excipients used in drug preparation.
Thus, excipients are carefully selected with regard to
their effect on the shelf-life of the drug product. 4,5
Oxidation
Most drugs (that is, APIs) are in their reduced form,
and oxygen, which participates in most oxidative
processes, is abundant in the environment.
Oxidation is a loss of electrons or an increase in the
oxidation state. Consequently, drug oxidation is
a common reason for decreased product shelf-lives.
Oxidative reactions proceed through free radicals
or free radical-like pathways. Metal ions and light
are known to catalyse oxidative drug degradation.
Steroids, most tricyclic compounds and sulfhydryl
compounds are susceptible to oxidation. Oxidative
reactions can be reduced by removal of oxygen
from the dosage forms, pH adjustments, using
chelating agents to complex metal ions, addition
of antioxidants, and exclusion of light. 4
Stability of parenteral solutions
Parenteral solutions are generally clear aqueous
solutions consisting of dissolved API and excipients.
They must be sterile and pyrogen-free, isotonic
solutions and free from visible particulate matter.
Whenever possible, their pH should be close
to the pH of normal blood plasma or 7.35–7.45
(that is, physiologic pH). In some cases, it is
necessary to deviate somewhat from physiologic
pH due to solubility and/or stability issues, and
there are products on the market with pH as
low as 2.5 (morphine sulfate injection) and as
high as 12 (phenytoin injection). However, such
large deviations from physiologic pH can cause
discomfort upon administration. In some cases,
parenteral solutions of poorly soluble drugs are
milky emulsions (for example, propofol injections)
or contain relatively high concentrations of organic
solvents such as propylene glycol (for example,
diazepam) but these are exceptions.
Example
The anticancer drug melphalan is an alkyl halide
that is rapidly hydrolysed and somewhat poorly
soluble in aqueous solutions. It is a base with
maximum solubility and chemical stability (t 90 ≈ 24
hours) at pH below 1. The solubility decreases and
rate of hydrolysis increases with increasing pH. At
physiologic pH, the aqueous solubility of melphalan
is about 0.05mg/ml. Due to its rapid hydrolysis (that
is, a very short t 90 ) the drug must be marketed as
sterile powder that is dissolved in normal saline
before injection. In the marketed product (Evomela ® )
sulfobutyl ether β-cyclodextrin is used to increase
the aqueous solubility and stability of the drug. The
shelf-life of the reconstituted solution is 24 h at 5°C
and 1 h at room temperature. 6
The physical and chemical stability can be
reduced when two or more parenteral solutions are
combined. Such changes are frequently referred
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TABLE 3
The main degradation pathways
Degradation pathway Example Drug
Hydrolysis Ester Aspirin
Lactam Benzylpenicillin
Oxidation OH-groups Ascorbic acid
Isomerisation Stereoisomers Tetracycline
Photochemical
degradation Photo/oxidation Piroxicam
Dehydration Prostaglandin
E 2
Polymerisation Ampicillin
to as incompatibilities. For example, dextrose
(glucose) catalyses hydrolytic degradation of
b-lactam antibiotics, thereby shortening the drug
shelf-life. Ampicillin has approximately 12-times
longer shelf-life in isotonic saline (aqueous 0.9% w/v
NaCl solution) than in aqueous 5% (w/v) dextrose
solution. 7 Likewise, the physical stability due to drug
precipitation can occur when drugs that have pH-
dependent solubility (such as melphalan) are mixed
with other parenteral solutions.